Role of Adiposomes in Diabetes-Associated Endothelial Dysfunction and Restorative Effects of Exercise and Metabolic Surgery

ABSTRACT The development of type II diabetes (T2D) is strongly associated with obesity, and both are well-established risk factors for cardiovascular disease. Vascular dysfunction is an early event in developing cardiovascular disease in obese diabetic (OB-T2D) patients. Therefore, we set our long-term goal to define molecular mechanisms of vascular dysfunction and corrective strategies that target these mechanisms, such as physical activity and weight loss. We recently discovered that human adipose tissues release extracellular vesicles (adiposomes) that are efficiently captured by endothelial cells. Adiposomes are known to carry bioactive cargos such as proteins and micro RNAs; however, their lipid content has not been studied, neither their ability to transfer their lipid cargo to endothelial cells. In the current application, we propose investigating the role of adiposomes in communicating the unhealthy milieu, mainly dysregulated lipids, to endothelial cells in OB-T2D subjects. On top of these lipid species that we propose to be carried by adiposomes are glycosphingolipids (GSLs). GSLs originate from ceramide glycosylation, a chemical process that is upregulated in the presence of inflammation and high glucose levels. Our preliminary findings showed that in endothelial cells, GSL-rich adiposomes disturb plasma membrane structure and subsequently induces endothelial dysfunction. Moreover, we found preconditioning endothelial cells with high shear stress (which is an exercise mimetic) protected endothelial cells from the detrimental effects caused by adiposomes. Therefore, our central hypothesis is that adipose tissues in OB-T2D patients release GSL-loaded adiposomes that induce vascular endothelial dysfunction. We propose that exercise and weight loss interventions (bariatric surgery) will restore adipose tissue homeostasis, reduce GSL-loaded adiposomes, and subsequently alleviate vascular risk in OB-T2D patients. We will test our hypotheses by pursuing the following Aims: Aim 1: Investigate the role of GSL-rich adiposomes in the pathogenesis of endothelial dysfunction in OB- T2D adults; Aim 2: Test the effectiveness of exercise training in reducing adiposome-mediated effects on vascular function; and Aim 3: Examine changes in adiposome/caveolae axis following metabolic surgery and their association with vascular function. This study will improve our mechanistic understanding of the biological underpinning of adiposome production, packaging, and role in inducing ED under conditions of obesity and T2D. It will also identify adiposomes and the proposed mechanisms of their interaction with endothelial cells as novel therapeutic targets for improving vascular function in OB-T2D individuals. Once these pathways are elucidated, strategies for targeting them can be advanced, leading to an improved therapeutic management of T2D-related cardiovascular disease.